ABSTRACT Over the past project periods we tracked the biological basis of cognitive decline and dementia to understand the heterogeneous contributions of a dozen brain pathologies to individuals in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). We identified numerous genomic, medical, experiential, and psychological factors associated with cognitive decline and incident Alzheimer?s dementia, and also neurobiologic pathways linking some of these factors to Alzheimer?s disease (AD) and to related dementias. In the most recent funding period, to understand the biological basis of risk factors, we analyzed multi-region multi-omic data to identify novel and potentially high value therapeutic targets for the treatment and prevention of AD and related dementias. The computational biology target nominations were validated with targeted proteomics. All data are well-organized and shared publically with stakeholders around the globe. The overall goal of the proposed continuation is to identify additional protein targets, and their splice isoforms and post-translational modifications (PTMs) that drive AD related traits and can serve as novel therapeutic targets. We focus specifically on the hippocampus and entorhinal cortex, a region that is a key hub in the neurodegenerative disease network. Further, several neurodegenerative disease pathologies including tau tangles, TDP-43, Lewy bodies, and hippocampal sclerosis, are far more common in these regions relative to the neocortical regions with existing omic data. Aim 1 will generate bulk and single cell RNAseq and deep tandem mass tag (TMT) proteomics which can now generate upwards of 10,000 unique proteins making it virtually genome-wide; it will use these data to identify cell type-specific molecular systems, i.e., dozens to hundreds of coexpressed genes and proteins. Aim 2 will identify the specific molecular systems that drive AD related traits; further, through integration of all omic data from all regions it will identify key drivers of these systems. This will nominate genes and proteins that could serve as therapeutic targets. Aim 3 will perform top-down proteomics to identify splice isoforms, proteolytic fragments, and post-translational modifications of select high value proteins. Secondary aims will continue to explore the biologic pathways linking risk factors to AD related traits which has been the main deliverable of this grant since its inception; it will also share the newly generated data with the wider AD research community. The proposal will deliver high value therapeutic targets which will be passed to the Accelerated Medicines Partnership-AD (AMP-AD) consortium for further study. Thus, the identification of these proteins will have a high and sustained impact on the field of aging and dementia.